7ufz

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure of TDP1 complexed with compound XZ768

Structural highlights

7ufz is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.559Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

TYDP1_HUMAN Defects in TDP1 are the cause of spinocerebellar ataxia autosomal recessive with axonal neuropathy (SCAN1) [MIM:607250. SCAN1 is an autosomal recessive cerebellar ataxia (ARCA) associated with peripheral axonal motor and sensory neuropathy, distal muscular atrophy, pes cavus and steppage gait as seen in Charcot-Marie-Tooth neuropathy. All affected individuals have normal intelligence.^[1] ^[2] ^[3] ^[4] ^[5]

Function

TYDP1_HUMAN DNA repair enzyme that can remove a variety of covalent adducts from DNA through hydrolysis of a 3'-phosphodiester bond, giving rise to DNA with a free 3' phosphate. Catalyzes the hydrolysis of dead-end complexes between DNA and the topoisomerase I active site tyrosine residue. Hydrolyzes 3'-phosphoglycolates on protruding 3' ends on DNA double-strand breaks due to DNA damage by radiation and free radicals. Acts on blunt-ended double-strand DNA breaks and on single-stranded DNA. Has low 3'exonuclease activity and can remove a single nucleoside from the 3'end of DNA and RNA molecules with 3'hydroxyl groups. Has no exonuclease activity towards DNA or RNA with a 3'phosphate.^[6] ^[7] ^[8] ^[9] ^[10]

Publication Abstract from PubMed

Tyrosyl-DNA phosphodiesterase 1 (TDP1) repairs stalled type I topoisomerase (TOP1)-DNA complexes by hydrolyzing the phosphodiester bond between the TOP1 Y723 residue and the 3'-phosphate of its DNA substrate. Although TDP1 antagonists could potentially reduce the dose of TOP1 inhibitors needed to achieve effective anticancer effects, the development of validated TDP1 inhibitors has proven to be challenging. This may, in part, be due to the open and extended nature of the TOP1 substrate binding region. We have previously reported imidazopyrazines and imidazopyridines that can inhibit TDP1 catalytic function in vitro. We solved the TDP1 crystal structures with bound inhibitors of this class and found that the dicarboxylic acid functionality within the N-(3,4-dicarboxyphenyl)-2-diphenylimidazo [1,2-a]pyridin-3-amine platform overlaps with aspects of phosphoryl substrate recognition. Yet phosphonic acids could potentially better-replicate cognate TOP1-DNA substrate binding interactions than carboxylic acids. As reported herein, we designed phosphonic acid-containing variants of our previously reported carboxylic acid-containing imidazopyrazine and imidazopyridine inhibitors and effected their synthesis using one-pot Groebke-Blackburn-Bienayme multicomponent reactions. We obtained crystal structures of TDP1 complexed with a subset of inhibitors. We discuss binding interactions of these inhibitors within the context of phosphate-containing substrate and carboxylic acid-based inhibitors. These compounds represent a new structural class of small molecule ligands that mimic aspects of the 3'-processed substrate that results from TDP1 catalysis.

Phosphonic acid-containing inhibitors of tyrosyl-DNA phosphodiesterase 1.,Zhao XZ, Wang W, Lountos GT, Tropea JE, Needle D, Pommier Y, Burke TR Jr Front Chem. 2022 Aug 16;10:910953. doi: 10.3389/fchem.2022.910953. eCollection , 2022. PMID:36051621^[11]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Interthal H, Chen HJ, Champoux JJ. Human Tdp1 cleaves a broad spectrum of substrates, including phosphoamide linkages. J Biol Chem. 2005 Oct 28;280(43):36518-28. Epub 2005 Aug 31. PMID:16141202 doi:M508898200
↑ Zhou T, Lee JW, Tatavarthi H, Lupski JR, Valerie K, Povirk LF. Deficiency in 3'-phosphoglycolate processing in human cells with a hereditary mutation in tyrosyl-DNA phosphodiesterase (TDP1). Nucleic Acids Res. 2005 Jan 12;33(1):289-97. Print 2005. PMID:15647511 doi:33/1/289
↑ Takashima H, Boerkoel CF, John J, Saifi GM, Salih MA, Armstrong D, Mao Y, Quiocho FA, Roa BB, Nakagawa M, Stockton DW, Lupski JR. Mutation of TDP1, encoding a topoisomerase I-dependent DNA damage repair enzyme, in spinocerebellar ataxia with axonal neuropathy. Nat Genet. 2002 Oct;32(2):267-72. Epub 2002 Sep 16. PMID:12244316 doi:10.1038/ng987
↑ Hirano R, Interthal H, Huang C, Nakamura T, Deguchi K, Choi K, Bhattacharjee MB, Arimura K, Umehara F, Izumo S, Northrop JL, Salih MA, Inoue K, Armstrong DL, Champoux JJ, Takashima H, Boerkoel CF. Spinocerebellar ataxia with axonal neuropathy: consequence of a Tdp1 recessive neomorphic mutation? EMBO J. 2007 Nov 14;26(22):4732-43. Epub 2007 Oct 18. PMID:17948061 doi:7601885
↑ Interthal H, Chen HJ, Kehl-Fie TE, Zotzmann J, Leppard JB, Champoux JJ. SCAN1 mutant Tdp1 accumulates the enzyme--DNA intermediate and causes camptothecin hypersensitivity. EMBO J. 2005 Jun 15;24(12):2224-33. Epub 2005 May 26. PMID:15920477 doi:7600694
↑ Inamdar KV, Pouliot JJ, Zhou T, Lees-Miller SP, Rasouli-Nia A, Povirk LF. Conversion of phosphoglycolate to phosphate termini on 3' overhangs of DNA double strand breaks by the human tyrosyl-DNA phosphodiesterase hTdp1. J Biol Chem. 2002 Jul 26;277(30):27162-8. Epub 2002 May 21. PMID:12023295 doi:10.1074/jbc.M204688200
↑ Raymond AC, Rideout MC, Staker B, Hjerrild K, Burgin AB Jr. Analysis of human tyrosyl-DNA phosphodiesterase I catalytic residues. J Mol Biol. 2004 May 14;338(5):895-906. PMID:15111055 doi:10.1016/j.jmb.2004.03.013
↑ Raymond AC, Staker BL, Burgin AB Jr. Substrate specificity of tyrosyl-DNA phosphodiesterase I (Tdp1). J Biol Chem. 2005 Jun 10;280(23):22029-35. Epub 2005 Apr 4. PMID:15811850 doi:M502148200
↑ Interthal H, Chen HJ, Champoux JJ. Human Tdp1 cleaves a broad spectrum of substrates, including phosphoamide linkages. J Biol Chem. 2005 Oct 28;280(43):36518-28. Epub 2005 Aug 31. PMID:16141202 doi:M508898200
↑ Gao R, Huang SY, Marchand C, Pommier Y. Biochemical characterization of human tyrosyl-DNA phosphodiesterase 2 (TDP2/TTRAP): a Mg(2+)/Mn(2+)-dependent phosphodiesterase specific for the repair of topoisomerase cleavage complexes. J Biol Chem. 2012 Aug 31;287(36):30842-52. doi: 10.1074/jbc.M112.393983. Epub, 2012 Jul 20. PMID:22822062 doi:10.1074/jbc.M112.393983
↑ Zhao XZ, Wang W, Lountos GT, Tropea JE, Needle D, Pommier Y, Burke TR Jr. Phosphonic acid-containing inhibitors of tyrosyl-DNA phosphodiesterase 1. Front Chem. 2022 Aug 16;10:910953. PMID:36051621 doi:10.3389/fchem.2022.910953

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7ufz"

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[7ufz]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7UFZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7UFZ FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=N7U:(4-{[(4S)-2-phenylimidazo[1,2-a]pyridin-3-yl]amino}phenyl)phosphonic+acid'>N7U</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.559&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=N7U:(4-{[(4S)-2-phenylimidazo[1,2-a]pyridin-3-yl]amino}phenyl)phosphonic+acid'>N7U</scene></td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7ufz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ufz OCA], [https://pdbe.org/7ufz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ufz RCSB], [https://www.ebi.ac.uk/pdbsum/7ufz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ufz ProSAT]</span></td></tr>
 </table>
@@ Line 20: / Line 21: @@
 </div>
 <div class="pdbe-citations 7ufz" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Phosphodiesterase 3D structures|Phosphodiesterase 3D structures]]
 == References ==
 <references/>

7ufz

From Proteopedia

Current revision

Crystal structure of TDP1 complexed with compound XZ768

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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